EP1600446B1 - New 3,3-dimethyl-5-cyano-benzoxepine derivatives useful for the preparation of 5-formyl-benzoxepine derivatives - Google Patents

New 3,3-dimethyl-5-cyano-benzoxepine derivatives useful for the preparation of 5-formyl-benzoxepine derivatives Download PDF

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Publication number
EP1600446B1
EP1600446B1 EP04291268A EP04291268A EP1600446B1 EP 1600446 B1 EP1600446 B1 EP 1600446B1 EP 04291268 A EP04291268 A EP 04291268A EP 04291268 A EP04291268 A EP 04291268A EP 1600446 B1 EP1600446 B1 EP 1600446B1
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EP
European Patent Office
Prior art keywords
dimethyl
cyano
formula
process according
dihydrobenzoxepine
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Expired - Lifetime
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EP04291268A
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German (de)
English (en)
French (fr)
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EP1600446A1 (en
Inventor
Michel Brunet
Guy Le Borgne
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Merck Sante SAS
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Merck Sante SAS
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Priority to EP04291268A priority Critical patent/EP1600446B1/en
Priority to ES04291268T priority patent/ES2297350T3/es
Priority to PT04291268T priority patent/PT1600446E/pt
Application filed by Merck Sante SAS filed Critical Merck Sante SAS
Priority to DE602004009544T priority patent/DE602004009544T2/de
Priority to PL04291268T priority patent/PL1600446T3/pl
Priority to AT04291268T priority patent/ATE375988T1/de
Priority to DK04291268T priority patent/DK1600446T3/da
Priority to SI200430567T priority patent/SI1600446T1/sl
Priority to PCT/EP2005/004472 priority patent/WO2005111012A1/en
Priority to ARP050102036A priority patent/AR049105A1/es
Publication of EP1600446A1 publication Critical patent/EP1600446A1/en
Application granted granted Critical
Publication of EP1600446B1 publication Critical patent/EP1600446B1/en
Priority to HR20080019T priority patent/HRP20080019T3/xx
Priority to CY20081100065T priority patent/CY1107144T1/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to 3,3-dimethyl-5-cyano-benzoxepine derivatives and their use for the preparation of 3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepine derivatives.
  • 3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepine derivatives are disclosed in EP 1140893 B1 and US 6596758 patents as intermediates for the preparation of 5-(3,3-dimethyl-2,3-dihydro benzoxepin-5-yl)-2,4-pentadienoic acid derivatives, which in turn are useful for treating dyslipidemias, atherosclerosis and diabetes.
  • This synthetic method involves four chemical steps starting from benzoxepinone and the yields, as reported, are moderate.
  • the compounds of formula (II) can be obtained in only three steps, each being characterized by high yields.
  • the invention provides an economical and efficient route for preparing the compounds of formula (II).
  • the present invention is related to compounds of general formula (I) :
  • Each of R is independently chosen from a halogen atom; a cyano group; a nitro group; a carboxy group; an optionally halogenated (C 1 -C 18 )alkoxycarbonyl group; an R a -CO-NH- or R a R b N-CO- group [in which R a and R b independently represent optionally halogenated (C 1 -C 18 )alkyl; a hydrogen atom; (C 6 -C 10 )aryl or (C 6 -C 10 )aryl(C 1 -C 5 )alkyl (where the aryl parts are optionally substituted by a halogen atom, by an optionally halogenated (C 1 -C 5 )alkyl group or by an optionally halogenated (C 1 -C 5 )alkoxy group); (C 3 -C 12 )cycloalkyl optionally substituted by a halogen atom, by an optionally halogenated (C
  • the formula (I) encompasses all types of geometric isomers and stereoisomers of the compounds of formula (I) or mixtures thereof.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched, having 1 to 18 carbon atoms in the chain. Preferred alkyl groups have 1 to 12 carbon atoms in the chain.
  • Branched alkyl means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.
  • “Lower alkyl” means an alkyl group with 1 to about 4 carbon atoms in the chain which may be straight or branched.
  • Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
  • the alkyl group may be substituted by one or more halogen atoms representing thus an "halogenoalkyl" group.
  • Halogen atoms means fluorine, chlorine, bromine or iodine atoms. Preferred are fluorine, chlorine or bromine atoms and more preferred is fluorine atoms.
  • halogenoalkyl groups may thus refer to “perfluoroalkyl", which means groups corresponding to the formula "-C n F 2n+1 " wherein n represents 1 to 18.
  • perfluoroalkyl groups are pentafluoroethyl or trifluoro-methyl.
  • Alkoxy means an alkyl-O- group wherein the alkyl group is as herein described.
  • exemplary alkoxy groups include methoxy, ethoxy, isopropyloxy, butoxy and hexyloxy radicals.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system of about 3 to 12 carbon atoms. Preferred ring sizes of the ring system include about 3 to 8 and more preferably 5 to 6 ring atoms.
  • the cycloalkyl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • Exemplary monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.
  • Exemplary multicyclic cycloalkyl include 1-decalyn, norbornyl and the like.
  • Cycloalkenyl means a non-aromatic mono- or multicyclic ring system of about 3 to about 12 carbon atoms, preferably of about 5 to about 10 carbon atoms, and which contain at least one carbon-carbon double bond. Preferred ring size of rings of the ring system include about 5 to about 6 ring atoms.
  • the cycloalkenyl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • Exemplary monocyclic cycloalkenyl include cyclopentenyl, cyclo-hexenyl, cycloheptenyl and the like.
  • An exemplary multicyclic cycloalkenyl is norbornylenyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system of about 6 to about 10 carbon atoms.
  • the aryl is optionally substituted with one or more "ring system substituents" which may be the same or different and are as defined herein.
  • Exemplary aryl groups include phenyl or naphtyl, or substituted phenyl or substituted naphtyl.
  • Alkenyl means an aliphatic hydrocarbon group containing one or more carbon-carbon double bond and which may be straight or branched, having about 2 to about 12 carbon atoms in the chain, and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched alkenyl means that one or more lower alkyl or alkenyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain.
  • Lower alkenyl means about 2 to about 4 carbon atoms in the chain, which may be straight or branched. The alkenyl group may be substituted by one or more halogen atoms.
  • Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexyl-butenyl and decenyl.
  • Aryloxy means an aryl-O- group wherein the aryl group is as defined herein.
  • exemplary groups include phenoxy and 2-naphtyloxy.
  • Aryloxycarbonyl means an aryl-O-CO- group wherein the aryl group is as defined herein.
  • exemplary aryloxycarbonyl groups include phenoxy-carbonyl and naphtoxycarbonyl.
  • Arylcarbonyl refers to an aryl-CO- group wherein the aryl group is as defined herein.
  • Exemplary arylcarbonyl group includes benzoyl.
  • the (C 6 -C 10 ) aryl, (C 3 -C 12 ) cycloalkyl, (C 3 -C 12 ) cycloalkenyl are optionally substituted by one or more "ring system substituents".
  • Ring system substituents mean substituents attached to aromatic or non-aromatic ring systems, inclusive of halogen atoms, an optionally halogenated (C 1 -C 5 ) alkyl, or an optionally halogenated (C 1 -C 5 ) alkoxy, halogen, alkyl and alkoxy being as defined herein,
  • aryl, cycloalkyl and cycloalkenyl parts are optionally substituted by a halogen atom, by an optionally halogenated (C 1 -C 5 )alkyl or by an optionally halogenated (C 1 -C 5 )alkoxy
  • aryl, cycloalkyl, cycloalkenyl groups are optionally substituted by one or more substituents selected from the group consisting of :
  • halogenated means, in the context of the description, optionally substituted by one or more halogen atoms.
  • each of R independently represents a halogen atom, an optionally substituted halogenated (C 6 -C 10 ) arylcarbonyl, an optionally halogenated (C 1 -C 18 ) alkyl, an optionally halogenated (C 1 -C 18 ) alkoxy, or an optionally halogenated (C 6 -C 10 ) aryl.
  • halogen atoms examples include fluorine, bromine and chlorine atoms.
  • optionally substituted halogenated (C 6 -C 10 ) arylcarbonyl include the groups ortho, meta or para chlorobenzoyl, or ortho, meta, para-bromobenzoyl.
  • Examples of preferred optionally halogenated (C 1 -C 18 ) alkyl include notably perfluoroalkyl groups such as trifluoromethyl.
  • Examples of preferred optionally halogenated (C 1 -C 18 ) alkoxy include notably optionally halogenated (C 1 -C 6 ) alkoxy, particularly (C 1 -C 4 ) alkoxy such as methoxy, ethoxy, isopropyloxy, n-butoxy, isobutoxy.
  • Examples of particularly preferred optionally halogenated (C 6 -C 10 ) aryl include notably phenyl.
  • R represents a (C 1 -C 18 ) alkoxy group, more preferably a (C 1 -C 4 ) alkoxy group and, most preferably, a methoxy group.
  • p is 1 or 2 and more preferably 1.
  • R may be located in position 6, 7, 8 or 9 on the benzoxepine structure, as represented hereafter.
  • Preferred compounds of formula (I) are chosen from:
  • a more preferred compound of formula (I) is 3,3-dimethyl-5-cyano-7-methoxy-2,3-dihydrobenzoxepine : as well as its geometric isomers and stereoisomers or mixtures thereof.
  • the compounds of formula (I) are used for the preparation of compounds of formula (II) according to scheme 2 :
  • the present invention is directed to a method for preparing compounds of formula (II), comprising :
  • the conversion of the compound of formula (I) into the compound of formula (II) is carried out in the presence of a reducing agent.
  • a reducing agent there is no particular restriction on the nature of the reducing agent used in this reaction and any reducing agent conventionally used in a reaction of this type may equally be used here, provided that it has no adverse effect on other parts of the molecule.
  • Suitable reducing agents for reducing the nitrile compound of formula (I) to aldehyde include metal hydride reducing agents such as LiAlH 4 , NaAlH 4 , LiAlH (Oalkyl) 3 , LiAlH 2 (Oalkyl) 2 , LiAlH(NR 2 ) 3 where R is H or an alkyl group and iPr 2 AlH, iBu 2 AlH, also called DIBAL-H, the DIBAL-H being particularly preferred.
  • Another suitable method for reducing the nitrile to aldehyde involves reacting the nitrile with HCl and SnCl 2 . More particularly, it generally involves treating the nitrile with HCl, reducing the formed intermediate with SnCl 2 and hydrolyzing the obtained imine to the corresponding aldehyde.
  • the amount of reducing agent is for example 1.0 to 2 moles and more preferably 1.1 to 1.5 moles relative to 1 mole of compound (I).
  • Suitable solvents for step a) are aromatic solvents, ethers, halogenated hydrocarbons and aliphatic hydrocarbons and mixtures thereof.
  • aromatic solvents examples include benzene, toluene, xylene and ethylbenzene.
  • ethers include dialkyl ethers such as diethyl ether, dibutyl ether, dioxane, tetrahydrofurane.
  • halogenated hydrocarbons include notably dichloromethane, chloroforme, 1,2-dichloroethane.
  • aliphatic hydrocarbons examples include notably pentane, hexane, heptane and octane.
  • anhydrous conditions are used.
  • step a) can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it has been found convenient to carry out the reaction at a temperature from about -20°C to room temperature and preferably from -10°C to 0°C.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period from about 5minutes to about 20 hours will usually be sufficient.
  • the method for preparing the compound of formula (II) further comprises the step of hydrolyzing the compound obtained in step a).
  • the method may generally lead to the intermediate formation of an imine derivative that may be hydrolyzed in order to give the aldehyde (II).
  • This hydrolysis is preferably performed in situ .
  • the following scheme 3 is given as an illustration of this reaction pathway and is not to be considered as limiting the invention in its scope.
  • the hydrolysis is performed under acid conditions.
  • Suitable acids for the hydrolysis of the compounds obtained in step a) include inorganic acids, such as hydrochloric acid, sulphuric acid, nitric acid and phosphoric acid ; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and paratoluenesulfonic acid.
  • inorganic acids such as hydrochloric acid, sulphuric acid, nitric acid and phosphoric acid
  • sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and paratoluenesulfonic acid.
  • Inorganic acids are most preferred and notably hydrochloric acid.
  • Excess amount of acid is generally used and the amount of acid is for example 5 to 10 moles relative to 1 mole of compound (I).
  • the mixture is stirred, for example for 0.5 hour to 2 hours and preferably for 1 hour to 1.5 hour.
  • the time required for each reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of reagents. However, provided that the reaction is effected under the preferred conditions outlined above, a period from about 0.5 hour to about 2 hours will usually be sufficient for the hydrolysis step.
  • the compounds thus prepared may be recovered from the reaction mixture by conventional means, for example the compounds may be recovered by distilling of the solvent from the reaction mixture or, if necessary, optionally after distilling of the solvent from the reaction mixture, pouring the residue into water, followed by extraction with a water-immiscible organic solvent and distilling of the solvent from the extract. Additionally, the product can, if desired, be further purified by various well known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
  • Preferred compounds of formula (II) which may conveniently be prepared starting from corresponding compounds of formula (I) according to the present invention can be chosen from the group consisting in:
  • the compounds useful according to the invention may be prepared by the application or adaptation of known methods, by which are meant methods used heretofore or described in the literature, for example those described by R. C. Larock in Comprehensive Organic Transformations, VCH Publishers, 1989.
  • the invention provides a method for preparing the compounds of formula (I) comprising :
  • the reaction of step i) consists in converting the cetone of formula (III) into the corresponding cyanohydrin.
  • This reaction requires the presence of CN- ions; these may be provided in a free form in the reaction mixture or, alternatively, may be obtained by using a species providing such CN- ions.
  • CN- ions include a alkali metal cyanide, such as NaCN or KCN, diethylaluminum cyanide (Et 2 AlCN) or trialkyl- or triaryl-silylcyanide.
  • Other suitable species include equivalents of trialkylsilylcyanide such as notably KCN-Me 3 SiCl ( Tetrahedron Asymmetry, 2001, 12(2), 279-286, Effenberger F., Oswald S. ), LiCN-Me 3 SiCl (Synthesis, 1986, 12, 1054-1055, Yoneda R., Santo K., Harusawa S., Kirihara T.).
  • the reaction is carried out in the presence of trialkylsilylcyanide such as trimethylsilylcyanide (Me 3 SiCN), trimethylsilylcyanide being most preferred.
  • trialkylsilylcyanide such as trimethylsilylcyanide (Me 3 SiCN), trimethylsilylcyanide being most preferred.
  • step i) When trialkylsilylcyanide or triarylsilylcyanide are used, it is particularly preferred to carry out the reaction of step i) in the presence of a Lewis acid or a base.
  • alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride
  • (C 1 -C 10 ) alkyllithium compounds such as methyllithium, butyllithium, hexyllithium
  • alkali metal alkoxides such as sodium methoxide and sodium ethoxide
  • alkali metal carbonates such as potassium carbonate and sodium carbonate.
  • the alkyllithium compounds and notably the butyllithium are particularly preferred.
  • Lewis acids or bases such as LiClO 4 , LiBF 4 , Zn(CN) 2 , ZnI 2 , KCN, Bu 4 NCN, DABCO (diazabicyclooctane),Ti(OiPr) 4 , CaF 2 , Lewis acid-amberlite-trimethylsilyl triflate.
  • the amount of base is generally catalytic and is for example 0.01 to 0.5 moles and preferably 0.1 to 0.25 moles relative to 1 mole of compound (III).
  • suitable solvents include hydrocarbons, such as hexane, cyclohexane, benzene, toluene and xylene; aprotic polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, pyridine. Of these, hexane and pyridine are particularly preferred.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it has been found convenient to carry out the reaction at a temperature from about room temperature (20°C) to 150°C, and more preferably of from 20°C to 50°C.
  • the molar ratio of CN- or the species providing CN- relative to compound (III) may vary from 1.0 to 1.5 equivalent, preferably from 1.05 to 1.25.
  • This hydrolysis can be carried out in situ, straight after step i).
  • acids suitable for said hydrolysis include, but are not limited to, hydrochloric acid, sulphuric acid, nitric acid and phosphoric acid ; trifluoroacetic acid ; sulphonic acid, such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid and paratoluene sulfonic acid.
  • the hydrolysis is preferably performed in the presence of a chlorinating agent such as phosphorus oxychloride (POCl 3 ), thionyl chloride (SOCl 2 ), sulfuryl chloride (SO 2 Cl 2 ) ; or in the presence of trifluoroacetic acid (CF 3 CO 2 H), paratoluene sulphonic acid and hydrochloric acid (gaz).
  • a chlorinating agent such as phosphorus oxychloride (POCl 3 ), thionyl chloride (SOCl 2 ), sulfuryl chloride (SO 2 Cl 2 )
  • CF 3 CO 2 H trifluoroacetic acid
  • paratoluene sulphonic acid and hydrochloric acid gaze
  • the molar ration of said chlorinating agent relative to compound of formula (III) is from 1 to 2 equivalents, preferably 1.5 equivalents.
  • step ii) can be conducted in situ, the same solvents as for step i) can be used.
  • suitable solvents include hydrocarbons, such as hexane, cyclohexane, benzene, toluene and xylene; aprotic polar solvents such as N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, pyridine. Of these, hexane and pyridine are particularly preferred.
  • the reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, it has been found convenient to carry out the reaction at a temperature from about room temperature (20°C) to 150°C, preferably of from 20°C to the boiling temperature of the solvent, more preferably 90°C.
  • the reaction can be conducted for a time sufficient to obtain a satisfactory reaction rate, usually between 1 and 10 hours.
  • the compounds thus prepared may be recovered from the reaction mixture by conventional means, for example the compounds may be recovered by distilling of the solvent from the reaction mixture or, if necessary, optionally after distilling of the solvent from the reaction mixture, pouring the residue into water, followed by extraction with a water-immiscible organic solvent and distilling of the solvent from the extract. Additionally, the product can, if desired, be further purified by various well known techniques, such as recrystallization, reprecipitation or the various chromatography techniques, notably column chromatography or preparative thin layer chromatography.
  • the reaction mixture is cooled to 50-60°C and poured onto a mixture of toluene and water previously cooled to approximately 0°C. After stirring at 20-25°C for half an hour, the aqueous phase is separated and the organic phase is washed successively with diluted aqueous sodium hydroxide - sodium hypochlorite mixture, aqueous sodium chloride, diluted aqueous sulphuric acid and aqueous sodium chloride.
  • the toluene solution is finely partially concentrated at atmospheric pressure, treated with active charcoal and used without further purification (yield : 65-83 %). MP : 72°C.
  • a toluene solution of compound (IA) (1 kg, 4.36 moles) is cooled to approximately -10°C and a 20% toluene solution of diisobutylaluminum hydride (3.41 kg, 1.1 eq.) is added while maintaining the temperature between -10°C and 0°C. The mixture is stirred at this temperature for 1 hour and the end of the reaction is controlled by TLC.
  • the reaction mixture is then poured onto 5N hydrochloric acid at such a rate that the temperature does not exceed 40°C.
  • the mixture is stirred for 1 hour and the aqueous phase is separated.
  • the organic phase is washed with water and concentrated to dryness under vacuum.
  • the residue is dissolved in ethanol and treated with an aqueous solution of sodium metabisulfite (1.32 kg, 1.6 eq.) at reflux for 3 hours.
  • the end of the reaction is controlled by TLC and the ethanol is removed by distillation.
  • the solution obtained is cooled, washed with toluene at approximately 30°C, cooled to 15°C and basified with 30% aqueous sodium hydroxide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP04291268A 2004-05-18 2004-05-18 New 3,3-dimethyl-5-cyano-benzoxepine derivatives useful for the preparation of 5-formyl-benzoxepine derivatives Expired - Lifetime EP1600446B1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
ES04291268T ES2297350T3 (es) 2004-05-18 2004-05-18 Nuevos derivados de 3,3-dimetil-5ciano-benzoxepina utiles para la preparacion de derivados de 5-formil-benzoxepina.
SI200430567T SI1600446T1 (sl) 2004-05-18 2004-05-18 Novi derivati 3,3-dimetil-5-ciano-benzoksepina, ki so uporabljivi za pripravo derivatov 5-formil-benzoksepina
DE602004009544T DE602004009544T2 (de) 2004-05-18 2004-05-18 Neue 3,3-Dimethyl-5-Cyano-Benzoxepinderivate verwendbar zur Herstellung von 5-Formyl-Benzoxepinderivaten
PL04291268T PL1600446T3 (pl) 2004-05-18 2004-05-18 Nowe pochodne 3,3-dimetylo-5-cyjano-benzoksepin użyteczne do otrzymywania pochodnych 5-formylo-benzoksepin
AT04291268T ATE375988T1 (de) 2004-05-18 2004-05-18 Neue 3,3-dimethyl-5-cyano-benzoxepinderivate verwendbar zur herstellung von 5-formyl- benzoxepinderivaten
DK04291268T DK1600446T3 (da) 2004-05-18 2004-05-18 Ny 3,3-dimethyl-5-cyano-benzoxepin-derivater anvendelige til fremstillingen af 5-formyl-benzoxepin- derivater
EP04291268A EP1600446B1 (en) 2004-05-18 2004-05-18 New 3,3-dimethyl-5-cyano-benzoxepine derivatives useful for the preparation of 5-formyl-benzoxepine derivatives
PT04291268T PT1600446E (pt) 2004-05-18 2004-05-18 Novos derivados de 3,3-dimetil-5-ciano-benzoxepina úteis para a preparação de derivados de 5-formil-benzoxepina
PCT/EP2005/004472 WO2005111012A1 (en) 2004-05-18 2005-04-27 New 3,3-dimethyl-5-cyano-benzoxepines derivatives useful for the preparation of 5-formyl-benzoxepine derivatives
ARP050102036A AR049105A1 (es) 2004-05-18 2005-05-18 Derivados de 3,3-dimetil-5-ciano-benzoxepinas utiles para la preparacion de derivados de 5-formil-benzoxepina
HR20080019T HRP20080019T3 (en) 2004-05-18 2008-01-15 New 3,3-dimethyl-5-cyano-benzoxepine derivatives useful for the preparation of 5-formyl-benzoxepine derivatives
CY20081100065T CY1107144T1 (el) 2004-05-18 2008-01-17 Νεα παραγωγα 3,3-διμεθυλο-5-κυανο-βενζοξεπινης χρησιμα για τη παρασκευη παραγωγων 5-φορμυλο-βενζοξεπινης

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP04291268A EP1600446B1 (en) 2004-05-18 2004-05-18 New 3,3-dimethyl-5-cyano-benzoxepine derivatives useful for the preparation of 5-formyl-benzoxepine derivatives

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EP1600446A1 EP1600446A1 (en) 2005-11-30
EP1600446B1 true EP1600446B1 (en) 2007-10-17

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EP04291268A Expired - Lifetime EP1600446B1 (en) 2004-05-18 2004-05-18 New 3,3-dimethyl-5-cyano-benzoxepine derivatives useful for the preparation of 5-formyl-benzoxepine derivatives

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EP (1) EP1600446B1 (es)
AR (1) AR049105A1 (es)
AT (1) ATE375988T1 (es)
CY (1) CY1107144T1 (es)
DE (1) DE602004009544T2 (es)
DK (1) DK1600446T3 (es)
ES (1) ES2297350T3 (es)
HR (1) HRP20080019T3 (es)
PL (1) PL1600446T3 (es)
PT (1) PT1600446E (es)
SI (1) SI1600446T1 (es)
WO (1) WO2005111012A1 (es)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2787789B1 (fr) * 1998-12-29 2002-06-14 Lipha Benzopyranes et benzoxepines utilisables dans le traitement de dyslipidemies, de l'atherosclerose et du diabete, compositions pharmaceutiques les contenant et procedes de preparations

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EP1600446A1 (en) 2005-11-30
DK1600446T3 (da) 2008-03-03
HRP20080019T3 (en) 2008-02-29
PL1600446T3 (pl) 2008-03-31
SI1600446T1 (sl) 2008-04-30
CY1107144T1 (el) 2012-10-24
ES2297350T3 (es) 2008-05-01
PT1600446E (pt) 2008-01-23
AR049105A1 (es) 2006-06-28
ATE375988T1 (de) 2007-11-15
DE602004009544T2 (de) 2008-08-07
DE602004009544D1 (de) 2007-11-29
WO2005111012A1 (en) 2005-11-24

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